tbuckley/cabot-search huggingface dataset:
Abstract 5526: State-of-the-art biobanking of gastroesophageal adenocarcinoma samples: Integrating non-viable biospecimens with 3D and 2D cell models and their characterization, validation, and utilization of cell models for precision oncology
Authors: Mingyang Iris Kong, Sanjima Pal, Julie Berube, France Bourdeau, Betty Giannias, Nicholas Bertos, Veena Sangwan, Lorenzo Ferri
Journal: Cancer Research (2023)

Abstract Traditionally, biobanking platforms have collected and stored non-viable biological specimens such as serum, plasma, and fresh-frozen or formalin-fixed paraffin-embedded (FFPE) tissues. These constitute key resources for clinical and contemporary genomics, transcriptomics, and proteomics studies. However, such specimens cannot be used for studies involving drug testing, high throughput target validation, and implementation for personalized medicine. Next-generation biobanking strategies rectify this issue by combining the collection of non-viable samples from patients with the propagation of viable tissue fractions as in vitro 2D and 3D cell models or in vivo xenograft models. Such cutting-edge biobanking strategies enable downstream cell-based high-throughput functional assays promoting the discovery of therapeutic targets or assessing treatment responses and resistance to treatment. Here, we provide comprehensive details of our establishment of a state-of-the-art biobanking platform for gastroesophageal adenocarcinoma (GEA) samples (n=389). Our approach opens new directions for understanding disease biology and conducting translational cancer studies. Patient-derived 2D cells (n=376), organoids (PDOs) (n=185), and xenografts (PDXs) (n= 99) included in our pipeline retain crucial features of the original human tumors, serving as valuable tools for clinical and experimental analyses in the context of precision oncology. We also discuss the entire approach of next-generation biobanking and emphasize the importance of integrating the propagation of PDOs and PDXs simultaneously. In addition, we explain each protocol optimized to propagate patient tissue-derived cell models. We validate that these models recapitulate tissue heterogeneity and are relevant preclinical models. Taken together, we described each approach used to develop one of the largest next-level biobanks for GEA. Citation Format: Mingyang Iris Kong, Sanjima Pal, Julie Berube, France Bourdeau, Betty Giannias, Nicholas Bertos, Veena Sangwan, Lorenzo Ferri. State-of-the-art biobanking of gastroesophageal adenocarcinoma samples: Integrating non-viable biospecimens with 3D and 2D cell models and their characterization, validation, and utilization of cell models for precision oncology. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5526.
Abstract 536: The role of CCN1 in mutant K-RAS addiction in pancreatic ductal adenocarcinoma
Authors: Archana De, Vijayalaxmi Gupta, Amlan Das, Arnab Ghosh, Inamul Haque, Laster Lau, Sushanta K. Banerjee, Snigdha Banerjee
Journal: Cancer Research (2023)

Abstract Mutant K-RAS addiction of pancreatic ductal adenocarcinoma cells (PDAC) coordinates their transformation, proliferation, and survival. Therefore, initially, it had an impression that targeting mutant K-RAS could be an ideal strategy for treating PDAC. However, after decades of studies, no effective RAS inhibitors reached the clinic, indicating that RAS-oncoprotein is an undruggable target in PDAC. Thus, identifying a new target linked with K-RAS signaling was most needed. Using genetically engineered cell lines and K-RAS-driven genetically engineered mouse models (KC or KPC) with or without pancreas-specific CCN1 conditional knockout background, we identified a positive feedback circuit between CCN1 and mutant K-RAS expression. Moreover, blocking this feedback via conditional knockout of CCN1 in the pancreas significantly reduced invasive phenotypes, PDAC growth, and metastasis in the lung in KC and KPC mice. Mechanistically we found that the K-RAS-CCN1 feedback circuit is regulated by microRNA miR-145 via a feedforward mechanism. Collectively, these studies highlight the clinical potential of targeting CCN1 in PDAC. (This work is supported by VA Merit grants). Citation Format: Archana De, Vijayalaxmi Gupta, Amlan Das, Arnab Ghosh, Inamul Haque, Laster Lau, Sushanta K. Banerjee, Snigdha Banerjee. The role of CCN1 in mutant K-RAS addiction in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 536.
Abstract 2732: A self-replicating RNA precision medicine approach to therapeutic protein delivery of narrow therapeutic index biomolecules
Authors: Zelanna Goldberg, Christian Maine, Gabrielle P. Dailey, Christine Domingo, Gaelle Picarda, Hunter Little, Annie Chou, Jessica Sparks, Darina Spasova, Shigeki Miyake-Stoner, Christopher A. Rabiola, Erika J. Crosby, Zachary C. Hartman, Herbert K. Lyerly, Nathaniel Wang, Parinaz Aliahmad
Journal: Cancer Research (2023)

Abstract Protein drug replacement using nucleic acid technologies has been a sought-after solution for in situ production of proteins with poor half-lives and challenging manufacturability. Linear mRNA approaches have failed clinically in this technological use case due to low levels of protein expression and poor durability. Self-replicating RNA (srRNA) is a new technology for expression of biotherapeutics combining the advantages of fully synthetic drug products with higher peak levels of protein expression with active expression persisting out to 49 days. RBI-2000 is a novel srRNA encapsulated in a lipid nanoparticle and encoding two distinct proteins on the same strand of RNA. The first protein is a pro-inflammatory multimeric cytokine to promote de novo immune cell generation and infiltration. The second molecule is a single chain high affinity protein antagonist of downstream mediators of the inflammasome to prevent sterile inflammation, aberrant angiogenesis, and tumor invasiveness. We selected a novel alphaviral vector which demonstrated an enhanced peak level of protein expression vs. the prototypical vector that has been used in other RNA products. These encoded proteins elicited a pharmacodynamic response that had no evidence of decay in the first 7 days following a single treatment down to doses of 0.01 mcg. Using an implanted MC38 tumor model, tumor control was obtained at the lowest, single dose tested at 0.1 mcg of RBI-2000. When tested in combination with a checkpoint inhibitor (CPI), a single dose of the CPI and a single dose of RBI-2000 at 10 mcg resulted in 80% tumor control in the mice (8/10 mice). Tumor re-challenge of the mice at a site distal to the original implantation showed 100% protection. Collectively, these data demonstrate the feasibility of novel srRNA vectors as a protein drug replacement approach including for the expression of complex, multimeric cocktails of proteins. Citation Format: Zelanna Goldberg, Christian Maine, Gabrielle P. Dailey, Christine Domingo, Gaelle Picarda, Hunter Little, Annie Chou, Jessica Sparks, Darina Spasova, Shigeki Miyake-Stoner, Christopher A. Rabiola, Erika J. Crosby, Zachary C. Hartman, Herbert K. Lyerly, Nathaniel Wang, Parinaz Aliahmad. A self-replicating RNA precision medicine approach to therapeutic protein delivery of narrow therapeutic index biomolecules [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2732.
Abstract 1301: Evolution of heterogenous BRAFi/MEKi+CDK4/6i resistance mechanisms and targeting site-specific resistant populations in metastatic cutaneous melanoma
Authors: Haley P. Wilson, Timothy J. Purwin, Claudia Capparelli, Phil F. Cheng, Mitch P. Levesque, Reinhard Dummer, Jessica Teh, Andrew E. Aplin
Journal: Cancer Research (2023)

Abstract Intrapatient heterogeneity among different metastatic sites contributes to targeted therapy resistance. Determining the proteomic profile of metastatic melanoma lesions that develop within the same patient could help elucidate adaptive mechanisms that drive tumor progression during therapy. Tumors that persist through treatment and colonize distant organs adapt to and rely on organ-specific microenvironments. To assess how protein expression is altered in cutaneous melanoma derived from different metastatic sites in a single patient, we utilized patient-derived BRAFi/MEKi and BRAFi/MEKi+CDK4/6i-treated samples from the LOGIC2 clinical trial. Eight cell lines were established from patient biopsies at chronological time points throughout treatment and subsequent post-mortem resection of the bone, ovary, and brain metastatic sites. While the initial metastatic tumor in the breast was BRAFV600E mutant, NRASQ61 mutations were acquired after treatment with CDK4/6i in the bone and ovary tumors. RPPA was performed on six of the cell lines to characterize site-specific differences in protein expression. We detected upregulation of ErbB3 in the brain metastatic tumor. Since neuregulin 1, a ligand for ErbB3, is abundant in brain tissue, we tested its ability to promote resistance to BRAFi/MEKi in melanoma brain metastases. Neuregulin 1 rescued the growth of brain metastasis cells and restored phospho-AKT and phospho-ERK1/2 levels in the presence of BRAFi/MEKi. Therefore, the ErbB3-Neuregulin axis may be targeted, for example by using ErbB3 inhibitors to improve response to MAPK inhibitors in melanoma brain metastases. Further studies aim to investigate the evolution of metastatic cutaneous melanoma longitudinally in response to targeted therapies. Site-specific signaling mechanisms will be functionally examined as possible avenues for metastasis-specific targeted therapies to improve patient outcomes. Citation Format: Haley P. Wilson, Timothy J. Purwin, Claudia Capparelli, Phil F. Cheng, Mitch P. Levesque, Reinhard Dummer, Jessica Teh, Andrew E. Aplin. Evolution of heterogenous BRAFi/MEKi+CDK4/6i resistance mechanisms and targeting site-specific resistant populations in metastatic cutaneous melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1301.
Abstract 2022: What can we learn from phosphoproteomics compared to transcriptomics in DNA damage and other processes
Authors: Gali Arad, Kirill Pevzner, Eran Seger, Tamar Geiger
Journal: Cancer Research (2023)

Abstract The advancement of sequencing technologies made unbiased whole genome and transcriptome studies ubiquitous in the cancer research field. However, these omics analysis methods do not describe post-transcriptional and post-translational levels. With the recent availability of large scale multi-omics datasets, we set out to study the correlation between phosphorylations, protein expression and gene expression. The goal of this analysis is to highlight the cases in which systematic characterization of the whole proteome and phosphoproteome can uncover insights that are undetected with RNA sequencing. The analysis described below applies RNA-protein-phosphorylation comparisons based on clinical cancer datasets. We make use of the large amount of data generated by the Clinical Proteomic Tumor Analysis Consortium (CPTAC), which generates unique phosphorylations, protein and mRNA expression data from the exact same samples. Correlation analysis between the phosphorylation-protein-RNA profiles highlights multiple differences among cancer types and functional pathways. We specifically focus on the various DNA damage response pathways which are mediated by kinase activity, and as expected, show modest mRNA-protein correlations. The protein-RNA discordance is further demonstrated when using an unsupervised clustering of the data based on protein or RNA. This analysis showed substantial differences in tumor classification and the cellular processes that differentiate between clusters. Altogether, this study demonstrates the opportunity presented by applying proteomics and phosphoproteomics techniques to study multiple systems that are at play in cancer biology, highlighting DNA damage response as a striking example. Citation Format: Gali Arad, Kirill Pevzner, Eran Seger, Tamar Geiger. What can we learn from phosphoproteomics compared to transcriptomics in DNA damage and other processes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2022.
Abstract 171: Prostate cancer organoids from KUCaP patient-derived xenograft(PDX) series enables us to genetic engineering human-derived cellular models
Authors: Takuro Sunada, Takayuki Goto, Takayuki Sumiyoshi, Akamatsu Shusuke, Takashi Kobayashi
Journal: Cancer Research (2023)

Abstract Introduction and Objectives Cancer organoids are expected to be valuable models that recapitulate intratumor heterogeneity and the phenotypic diversity of the disease ex vivo. However, the establishment rate of prostate cancer (PCa) organoids directly from clinical specimens are still low, and we need to improve. Patient-derived xenograft model (PDX) is widely used as a human-derived in vivo model, but genetic engineering is impossible, limiting its use. We aimed to develop a method to stably grow prostate cancer organoids from PDX and evaluate the feasibility of gene engineering using PDX-derived organoids. Materials and Methods KUCaP PDX series, which were established from castration-resistant prostate cancer patient tissues, were used to establish organoids. Eight organoids from eight models of KUCaP PDX were established and maintained for at least three passages. Organoids were reinjected into immunodeficient mice to establish organoid-derived xenograft (ODX) with 100% efficacy. We compared histopathological and molecular characteristics of primary patient tumors, PDX tumors, organoids, and ODX tumors. We conducted whole exome sequencing and RNA sequencing to assess the genomic profiles across the models. Firefly luciferase was introduced into organoids to show the feasibility of genetic engineering. Results Pathological findings were similar across the models derived from the same patient. WES analysis revealed most of the mutations detected in the matched patient tumors and organoids. Hierarchical clustering of RNA sequencing showed that the primary tumors, PDX tumors, organoids, and ODX tumors derived from the same patient cluster, which indicates that even after clonal selection during the establishment of organoids, the basic molecular feature of the model is maintained (Figure). Firefly luciferase was successfully introduced in seven out of seven tested organoids and imaged the ODX tumors from these organoids in vivo. Conclusions Organoids were established with a high success rate using PDX. Firefly luciferase was successfully introduced, showed the feasibility of genetic engineering using prostate cancer organoids. Matched PDX and organoids of PCa recapitulate the basic molecular features of primary human PCa. PDX-derived organoids of PCa, which enables genetic engineering of human-derived cellular models, which could be a valuable tool to enhance PCa research. Citation Format: Takuro Sunada, Takayuki Goto, Takayuki Sumiyoshi, Akamatsu Shusuke, Takashi Kobayashi. Prostate cancer organoids from KUCaP patient-derived xenograft(PDX) series enables us to genetic engineering human-derived cellular models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 171.
Abstract 2914: iPSC-derived CAR-NK cell therapy: nominating clinical candidate clones through integrated multi-functional analysis
Authors: Matthew S. Hall, Ohad Manor, Liam Campion, Chiamin Bullaughey, Barry A. Morse, Buddha Gurung, Luis Borges
Journal: Cancer Research (2023)

Abstract CNTY-101 is an induced Pluripotent Stem Cell (iPSC) derived Chimeric Antigen Receptor (CAR) NK cell clinical candidate for the treatment of B-cell malignancies. It incorporates six gene edits. A CAR targeting CD19 mediates tumor cell engagement and killing, the homeostatic cytokine IL-15 improves functional persistence, and EGFR acts as a safety switch, providing an antibody target for elimination of the engineered cells, if ever necessary. Further edits are designed to reduce graft rejection due to alloreactivity, including disruption of beta-2-microglobulin (B2M) to prevent major histocompatibility complex class I (MHC-I) surface expression, disruption of class II major histocompatibility complex transactivator (CIITA), and expression of HLA-E fused with B2M. Our data indicate that iPSC lines show significant functional variability dependent on the original somatic cell and donor used for reprogramming. Additional functional variability is induced when the iPSC are genetically edited and differentiated to NK cells. This complexity necessitates careful methodology for nominating clinical candidate clones with desirable functional attributes and presents an opportunity for future refinement. Here, we evaluate 28 clinical candidate clones for CNTY-101, integrating in-process data from genetic engineering, differentiation, and a battery of functional assays into a unified analysis framework. We find that the donor and the number of integrated transgene alleles (ex. monoallelic vs biallelic) have a large impact on clone function. In silico correction for donor and allele number reveals that transgene surface expression correlates with functions including short-term killing, serial-killing, and persistence. We show that IL-15 transgene expression, serial-killing, and persistence correlate along one functional axis, while CAR expression, short-term killing, and cytokine secretion correlate on a second functional axis. In addition, we identify biomarkers measured during the differentiation process that are correlated with functional performance, such as the level of CD94 surface expression and tumor killing. Finally, we discuss the application of functional multi-omics to candidate clone nomination for Century Therapeutics’ pipeline of future products. Citation Format: Matthew S. Hall, Ohad Manor, Liam Campion, Chiamin Bullaughey, Barry A. Morse, Buddha Gurung, Luis Borges. iPSC-derived CAR-NK cell therapy: nominating clinical candidate clones through integrated multi-functional analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2914.
Abstract 6264: NUV-868, a novel BD2-selective BET inhibitor, in combination with enzalutamide or olaparib, inhibits growth of solid tumor xenografts
Authors: Hitisha Patel, Jennifer Hertzog, Laura Heller, Spandana Vootukuri, Yan Zhang, Chris Miller, Gary Hattersley
Journal: Cancer Research (2023)

Abstract The bromodomain and extraterminal domain (BET) family of proteins play a vital role in gene transcription, making it an attractive therapeutic target for cancer. BET inhibitors can also combine with many anticancer agents to enhance activity. The bromodomains of the BET protein, BD1 and BD2, have unique functions and inhibiting either domain can result in differential responses. To date, non-selective BET inhibitors have failed during early clinical development due to significant on-target toxicity and limited benefit; however, selectively targeting specific bromodomains may result in a more favorable benefit/risk profile. NUV-868 is a novel and highly selective BD2 inhibitor of the BET protein family with ~1500-fold selectivity for BRD4-BD2 relative to BRD4-BD1. Herein, we describe NUV-868 and its activity in multiple in vitro and in vivo solid tumor models. Target engagement, selectivity of bromodomain inhibition, and regulation of BET-mediated gene expression were examined. Additionally, the antitumor activity of NUV-868 in combination with enzalutamide or olaparib was studied in tumor xenograft models of prostate, breast, and pancreatic cancer. NUV-868 demonstrated high selectivity for BD2 and regulated expression of several BET target genes. NUV-868 in combination with enzalutamide inhibited growth of several prostate cancer cell line- and patient-derived xenografts. NUV-868 in combination with olaparib inhibited tumor growth in models of breast, ovarian and pancreatic cancer. Our preclinical data demonstrate that NUV-868, a BD2-selective BET inhibitor, inhibits growth of tumor xenografts in combination with enzalutamide or olaparib and provides rationale for examination of these combinations in the clinic. An ongoing, phase 1 clinical study (NCT05252390) is evaluating NUV-868 as a monotherapy and in combination with olaparib or enzalutamide in patients with advanced solid tumors. Citation Format: Hitisha Patel, Jennifer Hertzog, Laura Heller, Spandana Vootukuri, Yan Zhang, Chris Miller, Gary Hattersley. NUV-868, a novel BD2-selective BET inhibitor, in combination with enzalutamide or olaparib, inhibits growth of solid tumor xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6264.
Abstract 539: Furin predicts prognosis and promotes PTC progression and metastasis via MEK-ERK axis
Authors: Pratheeshkumar Poyil, Abdul K. Siraj, Divya Padmaja, Sandeep Kumar Parvathareddy, Roxanne Diaz, Saravanan Thangavel, Rafia Begum, Wael Haqawi, Khadija Alobaisi, Falah Hassan Al-Mohanna, Saif S. Al-Sobhi, Fouad Al-Dayel, Khawla S. Al-Kuraya
Journal: Cancer Research (2023)

Abstract Furin belongs to the proprotein convertase family and its expression has been documented in various types of cancers, but its role in Thyroid cancer remains unclear. We investigated the expression of Furin in a large cohort of middle eastern PTC patient’s samples and explored its functional role and mechanism in PTC cell line in vitro and in vivo. Furin overexpression was observed in 44.6% of all PTC cases and it was significantly associated with aggressive clinicopathological parameters and poor outcome. We show that inactivation of Furin suppresses tumor growth, proliferation, migration, invasion, spheroid growth and progression of EMT in BRAF mutant cells, whereas its overexpression in BRAF wild-type PTC cell lines reversed the effect. Mechanistically, Furin inactivation caused MEK/ERK pathway suppression in BRAF mutant cells, while inhibition of MEK has no effect on Furin expression which suggest Furin is a functional upstream of MEK/ERK Pathway. Furthermore, study revealed the synergistic antitumor effect of Furin depletion and MEK inhibitor. These results indicate that Furin is an important prognostic marker and its inhibition can be a potential therapeutic target for aggressive PTC. Citation Format: Pratheeshkumar Poyil, Abdul K. Siraj, Divya Padmaja, Sandeep Kumar Parvathareddy, Roxanne Diaz, Saravanan Thangavel, Rafia Begum, Wael Haqawi, Khadija Alobaisi, Falah Hassan Al-Mohanna, Saif S. Al-Sobhi, Fouad Al-Dayel, Khawla S. Al-Kuraya. Furin predicts prognosis and promotes PTC progression and metastasis via MEK-ERK axis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 539.